title: Sonic hedgehog and notch signaling can cooperate to regulate neurogenic divisions of neocortical progenitors.
abstract: BACKGROUND
  Hedgehog (Hh) signaling is crucial for the generation and maintenance of both embryonic and adult stem cells, thereby regulating development and tissue homeostasis. In the developing neocortex, Sonic Hedgehog (Shh) regulates neural progenitor cell proliferation. During neurogenesis, radial glial cells of the ventricular zone (VZ) are the predominant neocortical progenitors that generate neurons through both symmetric and asymmetric divisions. Despite its importance, relatively little is known of the molecular pathways that control the switch from symmetric proliferative to differentiative/neurogenic divisions in neural progenitors.
  
  
  RESULTS
  Here, we report that conditional inactivation of Patched1, a negative regulator of the Shh pathway, in Nestin positive neural progenitors of the neocortex leads to lamination defects due to improper corticogenesis and an increase in the number of symmetric proliferative divisions of the radial glial cells. Hedgehog-activated VZ progenitor cells demonstrated a concomitant upregulation of Hes1 and Blbp, downstream targets of Notch signaling. The Notch signaling pathway plays a pivotal role in the maintenance of stem/progenitor cells and the regulation of glial versus neuronal identity. To study the effect of Notch signaling on Hh-activated neural progenitors, we inactivated both Patched1 and Rbpj, a transcriptional mediator of Notch signaling, in Nestin positive cells of the neocortex.
  
  
  CONCLUSIONS
  Our data indicate that by mid neurogenesis (embryonic day 14.5), attenuation of Notch signaling reverses the effect of Patched1 deletion on neurogenesis by restoring the balance between symmetric proliferative and neurogenic divisions. Hence, our results demonstrate that correct corticogenesis is an outcome of the interplay between the Hh and Notch signaling pathways.
authors.affiliation: The Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Richa K
authors.initials: RK
authors.lastname: Dave
authors.forename: Tammy
authors.initials: T
authors.lastname: Ellis
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Toumpas
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Robson
authors.forename: Elaine
authors.initials: E
authors.lastname: Julian
authors.forename: Christelle
authors.initials: C
authors.lastname: Adolphe
authors.forename: Perry F
authors.initials: PF
authors.lastname: Bartlett
authors.forename: Helen M
authors.initials: HM
authors.lastname: Cooper
authors.forename: Brent A
authors.initials: BA
authors.lastname: Reynolds
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Wainwright
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D002455:Cell Division / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology*; D055495:Neurogenesis / Q000235:genetics* / Q000502:physiology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011247:Pregnancy; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; C465570:Shh protein, mouse